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n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
A BS T R AC T
Background
Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80%
of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a
proximal intracranial arterial occlusion, and moderate-to-good collateral circulation.
Methods
The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time
from study CT of the head to first reperfusion was 84 minutes. The rate of functional
independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the
intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and
the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control
group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75).
The authors full names, academic degrees, and affiliations are listed in the Appendix. Address reprint requests to Dr.
Hill at the Calgary Stroke Program, Department of Clinical Neurosciences, Hotchkiss
Brain Institute, University of Calgary,
Foothills Hospital, Rm. 1242A, 1403 29th
Street NW, Calgary, AB T2N 2T9, Canada,
or at michael.hill@ucalgary.ca.
Drs. Goyal and Hill contributed equally to
this article.
*A complete list of sites and investigators in the Endovascular Treatment for
Small Core and Anterior Circulation
Proximal Occlusion with Emphasis on
Minimizing CT to Recanalization Times
(ESCAPE) trial is provided in the Supplementary Appendix, available at
NEJM.org.
This article was published on February 11,
2015, at NEJM.org.
N Engl J Med 2015;372:1019-30.
DOI: 10.1056/NEJMoa1414905
Copyright 2015 Massachusetts Medical Society.
Conclusions
Among patients with acute ischemic stroke with a proximal vessel occlusion, a small
infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and
others; ESCAPE ClinicalTrials.gov number, NCT01778335.)
n engl j med 372;11nejm.orgmarch 12, 2015
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The
n e w e ng l a n d j o u r na l
schemic stroke is a devastating condition with a high burden of neurologic disability and death. As a systemic treatment,
intravenous alteplase has been shown to be better
than conservative care.1,2 Among patients with a
proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days
after stroke onset or do not regain functional independence despite alteplase treatment.3,4 The
major reason for the limited efficacy of alteplase
is the modest rate of early reperfusion among
patients with a large-vessel occlusion.5,6
Local treatment of large-vessel occlusion began with intraarterial delivery of thrombolytic
drugs.7 The Prolyse in Acute Cerebral Thromboembolism (PROACT) II study was the first positive trial of endovascular treatment involving
patients with angiographically visualized occlusion of the middle cerebral artery.8 Unfortunately, subsequent trials did not confirm the
clinical benefit even with the addition of firstgeneration thrombectomy devices.3,9,10 Key lessons learned from these previous trials are the
need for proof of proximal vessel occlusion,11
rapid and effective imaging methods to exclude
patients with a large infarct core,12-14 an efficient workflow to achieve fast recanalization,15,16
and high reperfusion rates.17-19
Recent studies have shown the superiority of
retrievable stents over the previous generation of
thrombectomy devices.17,18 The recently reported
Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in
the Netherlands (MR CLEAN) used this technology, and the results of that trial showed clinical
benefit with endovascular treatment.4 The Endovascular Treatment for Small Core and Anterior
Circulation Proximal Occlusion with Emphasis on
Minimizing CT to Recanalization Times (ESCAPE)
trial was designed to test whether patients with
acute ischemic stroke, who were selected on the
basis of results of computed tomography (CT) and
CT angiography (CTA), would benefit from rapid
endovascular treatment involving contemporary
endovascular techniques.20
Me thods
Trial Design
of
m e dic i n e
Participants
All participants had standard assessments of demographic characteristics, medical history, laboratory values, and stroke severity (NIHSS score).
Details of the assessments have been published
previously20 and are also available in the study
protocol. The primary outcome the score on
the modified Rankin scale at 90 days after randomization was assessed by trained personnel
who were unaware of the treatment-group assignments. The modified Rankin scale is a graded interval scale (range, 0 [no symptoms] to 6 [death])
for the assessment of neurologic functional disability.32 Secondary and safety outcomes included early recanalization and reperfusion, intracranial hemorrhage, angiographic complications,
neurologic disability at 90 days, and death. Interpretation of the imaging was performed at an
external core laboratory by personnel who were
unaware of the treatment-group assignments (when
they interpreted the CT images), clinical data, and
outcomes. External, independent clinical monitors
validated the clinical data.
Statistical Analysis
1021
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Intervention
(N=165)
Control
(N=150)
71
70
Demographic characteristics
Age yr
Median
6081
6081
Interquartile range
86 (52.1)
79 (52.7)
144 (87.3)
131 (87.3)
Hypertension
105 (63.6)
108 (72.0)
Diabetes mellitus
33 (20.0)
39 (26.0)
Atrial fibrillation
61 (37.0)
60 (40.0)
Clinical characteristics
NIHSS score
Median
16
17
1320
1220
147
146
131159
125169
6.6
6.7
5.87.7
5.77.8
9 (810)
9 (810)
45/163 (27.6)
39/147 (26.5)
111/163 (68.1)
105/147 (71.4)
6/163 (3.7)
3/147 (2.0)
21 (12.7)
19 (12.7)
Interquartile range
Systolic blood pressure at hospital arrival mm Hg
Median
Interquartile range
Glucose level at hospital arrival mmol/liter
Median
Interquartile range
Imaging characteristics
ASPECTS on CT median (interquartile range)
Location of occlusion on CTA no./total no. (%)
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Table 1. (Continued.)
Variable
Intervention
(N=165)
Control
(N=150)
169
172
117285
119284
134
136
77247
76238
110
125
80142
89183
51
Interquartile range
3968
84
Interquartile range
65115
241
Interquartile range
176359
120 (72.7)
118 (78.7)
* The intervention group was assigned to endovascular treatment plus standard care, and the control group was assigned to standard care alone. CT denotes computed tomography, CTA CT angiography, ICA internal carotid artery,
and IV intravenous.
Race was self-reported.
Scores on National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more
severe neurologic deficits.
To convert the values to milligrams per deciliter, divide by 0.05551.
The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is an imaging measure of the extent of
ischemic stroke. Scores ranges from 0 to 10, with higher scores indicating a smaller infarct core (details are available
at www.aspectsinstroke.com).
In one participant in the intervention group, the location of the occlusion on CTA was not determined by the core laboratory. Occlusion of the ICA with involvement of the M1 middle-cerebral-artery segment could occur with or without
involvement of the A1 anterior-cerebral-artery segment (see Fig. S4 in the Supplementary Appendix). The M1 middlecerebral-artery segment extends from the origin to the site of bifurcation or trifurcation (the anterior temporal artery
is considered a branch of the M1 segment). The M2 middle-cerebral-artery segments extend from the site of bifurcation or trifurcation to the origin of the cortical branches.
** For the time from stroke onset to the start of IV alteplase, data were missing for 1 patient in the intervention group.
For the time from study CT to groin puncture, 161 patients were included in the analysis. For the time from study CT
to first reperfusion and the time from stroke onset to first reperfusion, 145 patients were included in the analysis.
First reperfusion was defined as the first visualization of reflow in the middle cerebral artery, usually on deployment
of a retrievable stent.
R e sult s
early termination of the study
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The
n e w e ng l a n d j o u r na l
A Overall
Control
(N=147)
10
Intervention
(N=164)
12
15
15
24
21
18
20
12
16
40
19
13
60
10
80
100
Patients (%)
6 3
19
10
39
10
13
2
Intervention
(N=45)
20
20
18
13
20
Treatment
Control
(N=116)
Intervention
(N=119)
12
13
0
21
20
16
21
18
40
13
18
60
21
18
80
7
100
Patients (%)
Figure 1. Scores on the Modified Rankin Scale at 90 Days in the Intentionto-Treat Population.
Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no
symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death.
Panel A shows the distribution of scores at 90 days in the intervention and
control groups in the overall trial population. A significant difference between the intervention and control groups was noted in the overall distribution of scores (unadjusted common odds ratio, indicating the odds of improvement of 1 point on the modified Rankin scale, 2.6; 95% confidence
interval, 1.7 to 3.8), favoring the intervention. Panel B shows the distribution of scores at 90 days in the intervention and control groups according
to status with respect to intravenous (IV) alteplase treatment. In this analysis, there was no evidence of heterogeneity of effect (P = 0.89 for interaction
by the Wald test).
primary outcome
m e dic i n e
group crossed over to receive endovascular treatment. In the intervention group, 14 participants
did not receive any interventional therapy. Four
participants (1.3%) were lost to follow-up; missing
data on outcomes in these participants were not
imputed (Fig. S1 in the Supplementary Appendix).
Baseline characteristics were similar in the
two treatment groups (Table 1, and Table S1 in
the Supplementary Appendix). Imaging protocol
violations, identified by personnel who interpreted the images at the core laboratory, occurred
in 26 participants (8.3%): 11 of 308 participants
in whom the ASPECTS could be evaluated (3.6%)
had a score of less than 6 on the ASPECTS scale,
20 of 315 participants (6.3%) had poor collateral
circulation, and 14 of 315 participants (4.4%)
had inappropriate target-vessel occlusion (some
participants had >1 protocol violation). Collateral circulation was assessed with the use of
multiphase CTA in a majority of participants. A
total of 56 participants (17.8%) were enrolled
with deferral of consent procedures. Monitoring
of appropriate source documentation materials
(with regard to informed consent, inclusion and
exclusion criteria, randomization information, demographic characteristics, and assessments at
baseline [NIHSS score and Barthel Index score]
and at day 90 [modified Rankin score, NIHSS
score, and Barthel Index score]) was completed
for all randomly assigned participants.
of
Analysis of the primary end point showed a common odds ratio (indicating the odds of improvement of 1 point on the modified Rankin scale) of
2.6 (95% confidence interval [CI], 1.7 to 3.8) favoring the intervention (P<0.001) (Fig. 1A and Table 2).
The median 90-day modified Rankin score was
2 in the intervention group and 4 in the control
group (P<0.001). The proportion of patients with a
modified Rankin score of 0 to 2 at 90 days was
53.0% in the intervention group and 29.3% in the
control group (rate ratio, 1.8; 95% CI, 1.4 to 2.4;
P<0.001). Mortality at 90 days was 10.4% in the
intervention group and 19.0% in the control
group (rate ratio, 0.5; 95% CI, 0.3 to 1.0; P = 0.04)
(Fig. S5 in the Supplementary Appendix). The
rate of symptomatic intracerebral hemorrhage
was 3.6% in the intervention group and 2.7% in
the control group (rate ratio, 1.4; 95% CI, 0.4 to
4.7; P = 0.75). Device-related or procedural complications were observed in 18 patients: 4 had a
nejm.org
Intervention
(N=165)
Control
(N=150)
Difference
(95% CI)*
Effect
Variable
Unadjusted Value
(95% CI)
Adjusted Value
(95% CI)
Common
odds ratio
2.6 (1.73.8)
3.1 (2.04.7)
87/164 (53.0)
43/147 (29.3)
23.8 (13.234.4)
Rate ratio
1.8 (1.42.4)
1.7 (1.32.2)
79/153 (51.6)
31/134 (23.1)
28.4 (17.839.2)
Rate ratio
2.2 (1.63.2)
2.1 (1.53.0)
94/163 (57.7)
49/146 (33.6)
24.1 (13.334.9)
Rate ratio
1.7 (1.32.2)
1.7 (1.32.2)
113/156 (72.4)
43/138 (31.2)
6 (314)
13 (618)
Beta
coefficient
4.0 (2.25.8)
4.1 (2.65.6)
2 (18)
8 (319)
Beta
coefficient
6.5 (3.29.8)
6.5 (3.59.6)
80 (6090)
65 (5080)
Beta
coefficient
9.4 (3.515.2)
9.9 (3.816.0)
serious adverse event and 14 had a nonserious 0 to 100, with higher scores indicating better
adverse event (Table 3, and Table S2 in the Sup- quality of life) was 80 versus 65 (Table 2).
plementary Appendix).
There was no evidence of heterogeneity of effect across any of the prespecified subgroups
secondary outcomes and subgroup analyses
(defined according to age, sex, baseline NIHSS
Secondary clinical and imaging end points fa- score, baseline ASPECTS, occlusion location, and
vored the intervention group. The rate of patients status with respect to alteplase treatment) or acwith a score on the Barthel Index of 95 to 100 at cording to the presence or absence of cervical
90 days was 57.7% in the intervention group ver- carotid occlusion. All variables showed a direcsus 33.6% in the control group, the rate of patients tion of effect in favor of the intervention (Fig. 2,
with a 90-day NIHSS score of 0 to 2 was 51.6% and Fig. S6 in the Supplementary Appendix). Howversus 23.1%, and the median 90-day score on the ever, the absolute proportion of good outcomes
EuroQoL Group 5-Dimension Self-Report Ques- varied substantially according to subgroup (Fig.
tionnaire (EQ-5D) visual-analogue scale (range, 1B, and Fig. S7 in the Supplementary Appendix).
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The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Intervention
(N=165)
Control
(N=150)
Difference
(95% CI)*
Rate Ratio
(95% CI)
17/164 (10.4)
28/147 (19.0)
8 (4.8)
16 (10.7)
6 (3.6)
4 (2.7)
3 (1.8)
1 (0.6)
In the control group, follow-up CTA was performed in 138 participants (median time from
symptom onset to follow-up CTA, 425 minutes
[interquartile range, 355 to 564]). Successful
recanalization (as defined by a core-laboratory
adjudicated modified Arterial Occlusive Lesion
score of 2 or 3 on CTA, indicating partial or
complete recanalization of the occluded artery)
was observed in 43 of 138 participants (31.2%):
41 of 110 (37.3%) who received intravenous alteplase and 2 of 28 (7%) who did not. (For details
on the modified Arterial Occlusive Lesion scale,
see Table S3 in the Supplementary Appendix.)
Discussion
We found that among participants with acute
ischemic stroke with a small infarct core, a proximal intracranial occlusion in the anterior circulation, and moderate-to-good intracranial collateral circulation, rapid endovascular treatment
improved the clinical outcome and reduced mortality. The trial confirms the benefit of endovascular treatment reported recently in the MR CLEAN
trial.4
The ESCAPE trial attempted to deliver rapid
endovascular therapy to patients who were selected for inclusion on the basis of imaging. Post
hoc analysis of the Interventional Management of
Stroke (IMS) III trial and the Solitaire FR Thrombectomy for Acute Revascularization (STAR)
trial showed that achieving faster reperfusion, as
Variable
Age
>80 yr
80 yr
ASPECTS
810
<8
Cervical carotid occlusion
Yes
No
IV alteplase
Received
Not received
NIHSS score at baseline
619
>19
Location of occlusion
ICA with involvement of the M1 MCA
segment
M1 MCA segment or all M2 MCA
segments
Time from stroke onset to randomization
180 min
>180 min
Sex
Male
Female
0
3.0 (1.36.8)
2.7 (1.74.3)
2.6 (1.74.1)
2.7 (1.07.2)
9.6 (2.635.5)
2.2 (1.43.3)
2.5 (1.64.0)
2.6 (1.15.9)
2.6 (1.64.2)
2.4 (1.15.3)
2.6 (1.25.9)
2.7 (1.74.4)
2.6 (1.54.5)
2.5 (1.44.5)
2.5 (1.44.5)
2.6 (1.54.4)
2
Control Better
10
Intervention Better
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The
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of
m e dic i n e
Appendix
The authors full names and academic degrees are as follows: Mayank Goyal, M.D., Andrew M. Demchuk, M.D., Bijoy K. Menon, M.D.,
Muneer Eesa, M.D., Jeremy L. Rempel, M.D., John Thornton, M.D., Daniel Roy, M.D., Tudor G. Jovin, M.D., Robert A. Willinsky, M.D.,
Biggya L. Sapkota, M.B., B.S., Dar Dowlatshahi, M.D., Ph.D., Donald F. Frei, M.D., Noreen R. Kamal, M.D., Walter J. Montanera, M.D.,
Alexandre Y. Poppe, M.D., C.M., Karla J. Ryckborst, R.N., Frank L. Silver, M.D., Ashfaq Shuaib, M.D., Donatella Tampieri, M.D., David
Williams, M.B., Ph.D., Oh Young Bang, M.D., Ph.D., Blaise W. Baxter, M.D., Paul A. Burns, M.B., Ch.B., M.D., Hana Choe, M.D., JiHoe Heo, M.D., Ph.D., Christine A. Holmstedt, D.O., Brian Jankowitz, M.D., Michael Kelly, M.D., Ph.D., Guillermo Linares, M.D.,
Jennifer L. Mandzia, M.D., Ph.D., Jai Shankar, M.D., Sung-Il Sohn, M.D., Richard H. Swartz, Ph.D., Philip A. Barber, M.B., Ch.B., M.D.,
Shelagh B. Coutts, M.B., Ch.B., M.D., Eric E. Smith, M.D., M.P.H., William F. Morrish, M.D., Alain Weill, M.D., Suresh Subramaniam,
M.D., Alim P. Mitha, M.D., John H. Wong, M.D., Mark W. Lowerison, M.Sc., Tolulope T. Sajobi, Ph.D., and Michael D. Hill, M.D.
The authors affiliations are as follows: the Departments of Radiology (M.G., B.K.M., M.E., P.A. Barber, W.F.M., M.D.H.), Clinical
Neurosciences (M.G., A.M.D., B.K.M., N.R.K., K.J.R., P.A. Barber, S.B.C., E.E.S., S.S., A.P.M., J.H.W., M.D.H.), and Community Health
Sciences (E.E.S., T.T.S., M.D.H.), the Hotchkiss Brain Institute (M.G., A.M.D., B.K.M., N.R.K., P.A. Barber, S.B.C., E.E.S., A.P.M.,
J.H.W., M.D.H.), and the Clinical Research Unit (M.W.L.), University of Calgary, Calgary, AB, the Departments of Neurosurgery (J.L.R.)
and Medicine (Neurology) (A.S.), University of Alberta, Edmonton, the Departments of Radiology (D.R., A.W.) and Neurosciences
(A.Y.P.), University of Montreal, and the Montreal Neurological Institute (D.T.), Montreal, the Department of Medical Imaging (R.A.W.)
and Division of Neurology, Department of Medicine, Toronto Western Hospital (F.L.S.), the Department of Medical Imaging, St. Michaels Hospital (W.J.M.), and the Department of Medicine, Sunnybrook Health Sciences Centre (R.H.S.), University of Toronto, Toronto, the Department of Neurology, University of Ottawa, Ottawa (D.D.), the Department of Medical Imaging, University of Saskatch-
1028
References
1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J
Med 1995;333:1581-7.
2. Emberson J, Lees KR, Lyden P, et al.
Effect of treatment delay, age, and stroke
severity on the effects of intravenous
thrombolysis with alteplase for acute
ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929-35.
3. Broderick JP, Palesch YY, Demchuk
AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for
stroke. N Engl J Med 2013;368:893-903.
[Erratum, N Engl J Med 2013;368:1265.]
4. Berkhemer OA, Fransen PS, Beumer
D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke.
N Engl J Med 2015;372:11-20. [Erratum,
N Engl J Med 2015;372:394.]
5. del Zoppo GJ, Poeck K, Pessin MS, et
al. Recombinant tissue plasminogen activator in acute thrombotic and embolic
stroke. Ann Neurol 1992;32:78-86.
6. Bhatia R, Hill MD, Shobha N, et al.
Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: realworld experience and a call for action.
Stroke 2010;41:2254-8.
7. Zeumer H, Hacke W, Ringelstein EB.
Local intraarterial thrombolysis in vertebrobasilar thromboembolic disease. AJNR
Am J Neuroradiol 1983;4:401-4.
8. Furlan A, Higashida R, Wechsler L, et
al. Intra-arterial prourokinase for acute
ischemic stroke the PROACT II study: a
randomized controlled trial. JAMA 1999;
282:2003-11.
9. Ciccone A, Valvassori L. Endovascular
treatment for acute ischemic stroke.
N Engl J Med 2013;368:2433-4.
10. Kidwell CS, Jahan R, Gornbein J, et al.
A trial of imaging selection and endovascular treatment for ischemic stroke.
N Engl J Med 2013;368:914-23.
11. Demchuk AM, Goyal M, Yeatts SD, et
al. Recanalization and clinical outcome
of occlusion sites at baseline CT angiography in the Interventional Management of
Stroke III trial. Radiology 2014;273:202-10.
12. Menon BK, dEsterre CD, Qazi EM, et
al. Multiphase CT angiography: a new
1029
J, et al. Thrombolysis-related hemorrhagic infarction: a marker of early reperfusion, reduced infarct size, and improved
outcome in patients with proximal middle cerebral artery occlusion. Stroke 2002;
33:1551-6.
39. Bradley EH, Curry LA, Webster TR, et
al. Achieving rapid door-to-balloon times:
how top hospitals improve complex clinical systems. Circulation 2006;113:107985.
40. Krumholz HM, Herrin J, Miller LE, et
al. Improvements in door-to-balloon time
in the United States, 2005 to 2010. Circulation 2011;124:1038-45.
Copyright 2015 Massachusetts Medical Society.
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